Camu-camu decreases hepatic steatosis and liver injury markers in overweight, hypertriglyceridemic individuals: A randomized crossover trial.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population with no effective drug treatments available. Previous animal studies reported that a polyphenol-rich extract from the Amazonian berry camu-camu (CC) prevented hepatic steatosis in a mouse model of diet-induced obesity. This study aims to determine the impact of CC on hepatic steatosis (primary outcome) and evaluate changes in metabolic and gut microbiota profiles (exploratory outcomes). A randomized, double-blind, placebo-controlled crossover trial is conducted on 30 adults with overweight and hypertriglyceridemia, who consume 1.5 g of CC capsules or placebo daily for 12 weeks. CC treatment decreases liver fat by 7.43%, while it increases by 8.42% during the placebo intervention, showing a significant difference of 15.85%. CC decreases plasma aspartate and alanine aminotransferases levels and promotes changes in gut microbiota composition. These findings support that polyphenol-rich prebiotic may reduce liver fat in adults with overweight, reducing the risk of developing NAFLD.

Translational approach to establish the cardiometabolic health effects and mechanisms of action of fish nutrients-it takes a village.

People use dietary supplements to offset nutritional deficiencies and manage metabolic dysfunction. While the beneficial effect of fish proteins on glucose homeostasis is well established, the ability of fish peptides to replicate the protein findings is less clear. With financial support from a programmatic Canadian Institutes of Health Research (CIHR) Team grant, we aimed to identify salmon peptide fractions (SPFs) with the potential to mitigate metabolic dysfunction. Additionally, the grant aims included assessing whether vitamin D, a nutrient commonly found in salmon, could potentiate the beneficial effects of salmon peptides. In parallel, technologies were developed to separate and filter the isolated peptides. We employed an integrative approach that combined nutritional interventions in animal models and human subjects to identify metabolic pathways regulated by salmon peptides and other fish nutrients. This combination of interdisciplinary expertise revealed that a SPF could be a therapeutic tool used in the prevention and management of cardiometabolic diseases. Herein, we present a perspective of our CIHR funded grant that utilized a translational approach to establish the cardiometabolic health effects and mechanisms of action of fish nutrients: from animal models to clinical trials.

Substituting Refined Sugars With Maple Syrup Decreases Key Cardiometabolic Risk Factors in Individuals With Mild Metabolic Alterations: A Randomized, Double-Blind, Controlled Crossover Trial.

BACKGROUND: Maple syrup, a minimally transformed sweetener rich in polyphenols, can exert a action and improve metabolic parameters in animal models. However, no randomized clinical trial has investigated this. OBJECTIVES: This study aims to determine whether replacing refined sugars with an equivalent quantity of maple syrup could decrease key cardiometabolic risk factors in individuals with mild metabolic alterations. METHODS: In a randomized, double-blind, controlled crossover trial with 42 overweight adults with mild cardiometabolic alterations, participants were instructed to substitute 5% of their total caloric intake from added sugars with either maple syrup or an artificially flavored sucrose syrup for 8 wk. The primary outcome included changes in glucose homeostasis, whereas secondary outcomes were changes in other cardiometabolic risk factors such as blood pressure, anthropometric indices, and blood lipid profiles. Exploratory outcomes involved analyzing changes in gut microbiota composition. RESULTS: Replacing refined sugars with maple syrup over 8 wk decreased the glucose area under the curve when compared with substituting refined sugars with sucrose syrup, as determined during the oral glucose tolerance test, leading to a significant difference between the intervention arms (-50.59 ± 201.92 compared with 29.93 ± 154.90; P < 0.047). Substituting refined sugar with maple syrup also significantly decreased android fat mass (-7.83 ± 175.05 g compared with 67.61 ± 206.71 g; P = 0.02) and systolic blood pressure (-2.72 ± 8.73 mm Hg compared with 0.87 ± 8.99 mm Hg; P = 0.03). No changes in the blood lipid profile were observed. As an exploratory outcome, we further observed that substituting refined sugars with maple syrup promoted selective taxonomic changes in the gut microbiota such as a significant reduction in the abundance of Klebsiella species and decreased microbial functions associated with bacterial-induced cytokine response, when compared with substitution with sucrose syrup. CONCLUSIONS: Substituting refined sugars with maple syrup in individuals with mild metabolic alterations result in a significantly greater reduction of key cardiometabolic risk factors compared with substitution with sucrose syrup, in association with specific changes in gut microbiota. The role of the gut microbiota in these effects remains to be further explored. This trial was registered at clinicaltrials.gov as NCT04117802.

Informing Evidence-based Practice in Nutritional Genomics: An Educational Needs Assessment of Nutrition Care Providers in Canada.

Purpose: To investigate why Canadian nutrition care providers choose, or not, to integrate nutritional genomics into practice, and to evaluate the nutritional genomics training/education experiences and needs of nutrition providers in Canada, while comparing those of dietitians to non-dietitians.Methods: A cross-sectional online survey was distributed across Canada from June 2021 to April 2022.Results: In total, 457 healthcare providers (HCPs) [n = 371 dietitians (81.2%)] met the inclusion criteria. The majority (n = 372; 82.1%) reported having no experience offering nutritional genomics to clients (n = 4 did not respond). Of the 81 respondents with experience (17.9%), the most common reason to integrate nutrigenetic testing into practice was the perception that clients would be more motivated to change their eating habits (70.4%), while the most common reason for not integrating such tests was the perception that the nutrigenetic testing process is too complicated (n = 313; 84.1%). Dietitians were more likely than non-dietitians to view existing scientific evidence as an important educational topic (p = 0.002). The most selected useful educational resource by all HCPs was clinical practice guidelines (n = 364; 85.4%).Conclusions: Both dietitians and non-dietitians express a desire for greater nutritional genomics training/education; specific educational needs differ by type of HCP. Low implementation of nutrigenetic testing may be partly attributed to other identified barriers.

Genetic assessment of efficacy and safety profiles of coagulation cascade proteins identifies Factors II and XI as actionable anticoagulant targets.

Aims: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. Methods and results: To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, P = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, P = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, P = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, P = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, P = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, P = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses. Conclusion: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.

Corrigendum: Revisiting multi-omics-based predictors of the plasma triglyceride response to an omega-3 fatty acid supplementation.

[This corrects the article DOI: 10.3389/fnut.2024.1327863.].

Metabolic-associated fatty liver disease is characterized by a post-oral glucose load hyperinsulinemia in individuals with mild metabolic alterations.

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remain unclear. We compared the glucose metabolism, insulin resistance, insulin secretion, and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a body mass index (BMI) between 25 and 40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5.5-6.9 mmol/L, or glycated hemoglobin 5.7-5.9%. Participants were grouped according to MAFLD status, defined as hepatic fat fraction (HFF) ≥5% on MRI. We used oral minimal model on a frequently sampled 3 h 75 g-OGTT to estimate insulin sensitivity, insulin secretion, and pancreatic ß-cell function. Fifty percent of participants had MAFLD. Median age (IQR) [57 (45-65) vs. 57 (44-63) yr] and sex (60% vs. 56% female) were comparable between groups. Post-OGTT glucose concentrations did not differ between groups, whereas post-OGTT insulin concentrations were higher in the MAFLD group (P < 0.03). Individuals with MAFLD exhibited lower insulin clearance, insulin sensitivity, and first-phase pancreatic ß-cell function. In all individuals, increased insulin incremental area under the curve and decreased insulin clearance were associated with HFF after adjusting for age, sex, and BMI (P < 0.02). Among individuals with metabolic alterations, the presence of MAFLD was characterized mainly by post-OGTT hyperinsulinemia and reduced insulin clearance while exhibiting lower first phase ß-cell function and insulin sensitivity. This suggests that MAFLD is linked with impaired insulin metabolism that may precede T2D.NEW & NOTEWORTHY Using an oral glucose tolerance test, we found hyperinsulinemia, lower insulin sensitivity, lower insulin clearance, and lower first-phase pancreatic ß-cell function in individuals with MAFLD. This may explain part of the increased risk of incident type 2 diabetes in this population. These data also highlight implications of hyperinsulinemia and impaired insulin clearance in the progression of MAFLD to type 2 diabetes.

Revisiting multi-omics-based predictors of the plasma triglyceride response to an omega-3 fatty acid supplementation.

Background: The aim of the present study was to identify the metabolomic signature of responders and non-responders to an omega-3 fatty acid (n-3 FA) supplementation, and to test the ability of a multi-omics classifier combining genomic, lipidomic, and metabolomic features to discriminate plasma triglyceride (TG) response phenotypes. Methods: A total of 208 participants of the Fatty Acid Sensor (FAS). Study took 5 g per day of fish oil, providing 1.9-2.2 g eicosapentaenoic acid (EPA) and 1.1 g docosahexaenoic (DHA) daily over a 6-week period, and were further divided into two subgroups: responders and non-responders, according to the change in plasma TG levels after the supplementation. Changes in plasma levels of 6 short-chain fatty acids (SCFA) and 25 bile acids (BA) during the intervention were compared between subgroups using a linear mixed model, and the impact of SCFAs and BAs on the TG response was tested in a mediation analysis. Genotyping was conducted using the Illumina Human Omni-5 Quad BeadChip. Mass spectrometry was used to quantify plasma TG and cholesterol esters levels, as well as plasma SCFA and BA levels. A classifier was developed and tested within the DIABLO framework, which implements a partial least squares-discriminant analysis to multi-omics analysis. Different classifiers were developed by combining data from genomics, lipidomics, and metabolomics. Results: Plasma levels of none of the SCFAs or BAs measured before and after the n-3 FA supplementation were significantly different between responders and non-responders. SCFAs but not BAs were marginally relevant in the classification of plasma TG responses. A classifier built by adding plasma SCFAs and lipidomic layers to genomic data was able to even the accuracy of 85% shown by the genomic predictor alone. Conclusion: These results inform on the marginal relevance of SCFA and BA plasma levels as surrogate measures of gut microbiome in the assessment of the interindividual variability observed in the plasma TG response to an n-3 FA supplementation. Genomic data still represent the best predictor of plasma TG response, and the inclusion of metabolomic data added little to the ability to discriminate the plasma TG response phenotypes.

Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk.

BACKGROUND AND AIMS: RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. METHODS: RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. RESULTS: In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). CONCLUSIONS: PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.

Impact of maternal cardiometabolic status after bariatric surgery on the association between telomere length and adiposity in offspring.

The impact of bariatric surgery on metabolic and inflammatory status are reflected in the epigenetic profile and telomere length mediated by the changes in the metabolic status of the patients. This study compared the telomere length of children born before versus after maternal bariatric surgery as a surrogate to test the influence of the mother's metabolic status on children's telomere length. DNA methylation telomere length (DNAmTL) was estimated from Methylation-EPIC BeadChip array data from a total of 24 children born before and after maternal bariatric surgery in the greater Quebec City area. DNAmTL was inversely associated with chronological age in children (r = - 0.80, p < 0.001) and significant differences were observed on age-adjusted DNAmTL between children born before versus after the maternal bariatric surgery. The associations found between body mass index and body fat percentage with DNAmTL in children born after the surgery were influenced by maternal triglycerides, TG/HDL-C ratio and TyG index. This study reports the impact of maternal bariatric surgery on offspring telomere length. The influence of maternal metabolic status on the association between telomere length and markers of adiposity in children suggests a putative modulating effect of bariatric surgery on the cardiometabolic risk in offspring.

Heuristic Approach Uncovering Biological Significance of Gene-Lifestyle Interactions in Cardiometabolic Traits.

BACKGROUND: Gene-lifestyle interaction studies using genome-wide association studies (GWAS) data contribute to a better understanding of individual responses to environmental exposures. OBJECTIVES: Herein, we aimed at assessing the biological significance of overlapping genes reported in gene-lifestyle interaction studies in cardiometabolic health. METHOD: A heuristic analysis of genes reporting significant interactions related to cardiometabolic traits was performed to determine the biological pathways common to the different traits. RESULTS: A total of 873 genes were analyzed. Fine and condensed phenotypic solutions were obtained from overlapping genes common to more than one trait. CONCLUSIONS: This study revealed significant metabolic pathways associated with the impact of gene-environment interactions on cardiometabolic risk. Graphical Abstract: Publicly available data in cloud-based repositories were used to perform enrichment analyses of genes previously described in GWAS studies that showed interaction with lifestyles. From the enriched pathways, cluster analysis was performed to group enriched metabolic disorders.

A discriminant analysis of plasma metabolomics for the assessment of metabolic responsiveness to red raspberry consumption.

Background: Many studies show that the intake of raspberries is beneficial to immune-metabolic health, but the responses of individuals are heterogeneous and not fully understood. Methods: In a two-arm parallel-group, randomized, controlled trial, immune-metabolic outcomes and plasma metabolite levels were analyzed before and after an 8-week red raspberry consumption. Based on partial least squares discriminant analysis (PLS-DA) on plasma xenobiotic levels, adherence to the intervention was first evaluated. A second PLS-DA followed by hierarchical clustering was used to classify individuals into response subgroups. Clinical immune and metabolic outcomes, including insulin resistance (HOMA-IR) and sensitivity (Matsuda, QUICKI) indices, during the intervention were assessed and compared between response subgroups. Results: Two subgroups of participants, type 1 responders (n = 17) and type 2 responders (n = 5), were identified based on plasma metabolite levels measured during the intervention. Type 1 responders showed neutral to negative effects on immune-metabolic clinical parameters after raspberry consumption, and type 2 responders showed positive effects on the same parameters. Changes in waist circumference, waist-to-hip ratio, fasting plasma apolipoprotein B, C-reactive protein and insulin levels as well as Matsuda, HOMA-IR and QUICKI were significantly different between the two response subgroups. A deleterious effect of two carotenoid metabolites was also observed in type 1 responders but these variables were significantly associated with beneficial changes in the QUICKI index and in fasting insulin levels in type 2 responders. Increased 3-ureidopropionate levels were associated with a decrease in the Matsuda index in type 2 responders, suggesting that this metabolite is associated with a decrease in insulin sensitivity for those subjects, whereas the opposite was observed for type 1 responders. Conclusion: The beneficial effects associated with red raspberry consumption are subject to inter-individual variability. Metabolomics-based clustering appears to be an effective way to assess adherence to a nutritional intervention and to classify individuals according to their immune-metabolic responsiveness to the intervention. This approach may be replicated in future studies to provide a better understanding of how interindividual variability impacts the effects of nutritional interventions on immune-metabolic health.

Update of a Genetic Risk Score Predictive of the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation in the FAS Study.

A genetic risk score (GRS) predictive of the plasma triglyceride (TG) response to an omega-3 fatty acid (n-3 FA) supplementation has been previously developed in the Fatty Acid Sensor (FAS) Study. Recently, novel single nucleotide polymorphisms (SNPs) interacting with a fish oil supplementation and associated with plasma lipid levels have been identified in the UK Biobank. The aim of this study was to verify whether the addition of SNPs identified in the UK Biobank to the GRS built in the FAS Study improves its capacity to predict the plasma TG response to an n-3 FA supplementation. SNPs interacting with fish oil supplementation in the modulation of plasma lipid levels in the UK Biobank and associated with plasma TG levels have been genotyped in participants of the FAS Study (n = 141). Participants have been supplemented with 5 g fish oil/day for six weeks. Plasma TG concentrations were measured before and after the supplementation. Based on the initial GRS of 31 SNPs (GRS31), we computed three new GRSs by adding new SNPs identified in the UK Biobank: GRS32 (rs55707100), GRS38 (seven new SNPs specifically associated with plasma TG levels), and GRS46 (all 15 new SNPs associated with plasma lipid levels). The initial GRS31 explained 50.1% of the variance in plasma TG levels during the intervention, whereas GRS32, GRS38, and GRS46 explained 49.1%, 45.9%, and 45%, respectively. A significant impact on the probability of being classified as a responder or a nonresponder was found for each of the GRSs analyzed, but none of them outperformed the predictive capacity of GRS31 in any of the metrics analyzed, i.e., accuracy, area under the response operating curve (AUC-ROC), sensitivity, specificity and McFadden's pseudo R2. The addition of SNPs identified in the UK Biobank to the initial GRS31 did not significantly improve its capacity to predict the plasma TG response to an n-3 FA supplementation. Thus, GRS31 still remains the most precise tool so far by which to discriminate the individual responsiveness to n-3 FAs. Further studies are needed in the field to increase our knowledge of factors underlying the heterogeneity observed in the metabolic response to an n-3 FA supplementation.

Mendelian randomization prioritizes abdominal adiposity as an independent causal factor for liver fat accumulation and cardiometabolic diseases.

Background: Observational studies have linked adiposity and especially abdominal adiposity to liver fat accumulation and non-alcoholic fatty liver disease. These traits are also associated with type 2 diabetes and coronary artery disease but the causal factor(s) underlying these associations remain unexplored. Methods: We used a multivariable Mendelian randomization study design to determine whether body mass index and waist circumference were causally associated with non-alcoholic fatty liver disease using publicly available genome-wide association study summary statistics of the UK Biobank (n = 461,460) and of non-alcoholic fatty liver disease (8434 cases and 770,180 control). A multivariable Mendelian randomization study design was also used to determine the respective causal contributions of waist circumference and liver fat (n = 32,858) to type 2 diabetes and coronary artery disease. Results: Using multivariable Mendelian randomization we show that waist circumference increase non-alcoholic fatty liver disease risk even when accounting for body mass index (odd ratio per 1-standard deviation increase = 2.35 95% CI = 1.31-4.22, p = 4.2e-03), but body mass index does not increase non-alcoholic fatty liver disease risk when accounting for waist circumference (0.86 95% CI = 0.54-1.38, p = 5.4e-01). In multivariable Mendelian randomization analyses accounting for liver fat, waist circumference remains strongly associated with both type 2 diabetes (3.27 95% CI = 2.89-3.69, p = 3.8e-80) and coronary artery disease (1.66 95% CI = 1.54-1.8, p = 3.4e-37). Conclusions: These results identify waist circumference as a strong, independent, and causal contributor to non-alcoholic fatty liver disease, type 2 diabetes and coronary artery disease, thereby highlighting the importance of assessing body fat distribution for the prediction and prevention of cardiometabolic diseases.

Impact of Blueberry Consumption on the Human Fecal Bileacidome: A Pilot Study of Bile Acid Modulation by Freeze-Dried Blueberry.

Cholesterol-derived bile acids (BAs) affect numerous physiological functions such as glucose homeostasis, lipid metabolism and absorption, intestinal inflammation and immunity, as well as intestinal microbiota diversity. Diet influences the composition of the BA pool. In the present study, we analyzed the impact of a dietary supplementation with a freeze-dried blueberry powder (BBP) on the fecal BA pool composition. The diet of 11 men and 13 women at risk of metabolic syndrome was supplemented with 50 g/day of BBP for 8 weeks, and feces were harvested before (pre) and after (post) BBP consumption. BAs were profiled using liquid chromatography coupled with tandem mass spectrometry. No significant changes in total BAs were detected when comparing pre- vs. post-BBP consumption samples. However, post-BBP consumption samples exhibited significant accumulations of glycine-conjugated BAs (p = 0.04), glycochenodeoxycholic (p = 0.01), and glycoursodeoxycholic (p = 0.01) acids, as well as a significant reduction (p = 0.03) in the secondary BA levels compared with pre-BBP feces. In conclusion, the fecal bileacidome is significantly altered after the consumption of BBP for 8 weeks. While additional studies are needed to fully understand the underlying mechanisms and physiological implications of these changes, our data suggest that the consumption of blueberries can modulate toxic BA elimination.

Appraisal of Gene-Environment Interactions in GWAS for Evidence-Based Precision Nutrition Implementation.

PURPOSE OF REVIEW: This review aims to analyse the currently reported gene-environment (G × E) interactions in genome-wide association studies (GWAS), involving environmental factors such as lifestyle and dietary habits related to metabolic syndrome phenotypes. For this purpose, the present manuscript reviews the available GWAS registered on the GWAS Catalog reporting the interaction between environmental factors and metabolic syndrome traits. RECENT FINDINGS: Advances in omics-related analytical and computational approaches in recent years have led to a better understanding of the biological processes underlying these G × E interactions. A total of 42 GWAS were analysed, reporting over 300 loci interacting with environmental factors. Alcohol consumption, sleep time, smoking habit and physical activity were the most studied environmental factors with significant G × E interactions. The implementation of more comprehensive GWAS will provide a better understanding of the metabolic processes that determine individual responses to environmental exposures and their association with the development of chronic diseases such as obesity and the metabolic syndrome. This will facilitate the development of precision approaches for better prevention, management and treatment of these diseases.

Gene expression signatures and cardiometabolic outcomes following 8-week mango consumption in individuals with overweight/obesity.

Background: Little is known about the impact of mango consumption on metabolic pathways assessed by changes in gene expression. Methods: In this single-arm clinical trial, cardiometabolic outcomes and gene expression levels in whole blood samples from 26 men and women were examined at baseline and after 8 weeks of mango consumption and differential gene expression changes were determined. Based on changes in gene expression profiles, partial least squares discriminant analysis followed by hierarchical clustering were used to classify participants into subgroups of response and differences in gene expression changes and in cardiometabolic clinical outcomes following the intervention were tested. Results: Two subgroups of participants were separated based on the resemblance of gene expression profiles in response to the intervention and as responders (n = 8) and non-responders (n = 18). A total of 280 transcripts were significantly up-regulated and 603 transcripts down-regulated following the intervention in responders, as compared to non-responders. Several metabolic pathways, mainly related to oxygen and carbon dioxide transport as well as oxidative stress, were found to be significantly enriched with differentially expressed genes. In addition, significantly beneficial changes in hip and waist circumference, c-reactive protein, HOMA-IR and QUICKI indices were observed in responders vs. non-responders, following the intervention. Conclusion: The impact of mango consumption on cardiometabolic health appears to largely rely on interindividual variability. The novel transcriptomic-based clustering analysis used herein can provide insights for future research focused on unveiling the origins of heterogeneous responses to dietary interventions. Clinical Trial Registration: [clinicaltrials.gov], identifier [NCT03825276].

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity.

Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepatic BCKDK expression are associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKAs, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 patients with bariatric surgery with severe obesity and scored liver biopsy samples. Metabolite principal component analysis factors, BCKAs, branched-chain amino acids (BCAAs), and the BCKA/BCAA ratio were tested for associations with steatosis grade and presence of nonalcoholic steatohepatitis (NASH). Of all analytes tested, only the Val-derived BCKA, α-keto-isovalerate, and the BCKA/BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from 2 independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowered BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.

Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers.

BACKGROUND: There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers of the identified signals, as well as their potential functional roles. METHODS: Epigenome-wide association analyses were carried out to determine visceral fat mass-associated differentially methylated positions (VF-DMPs) in SAT samples from 538 TwinsUK participants. Validation and replication were performed in 333 individuals from 3 independent cohorts. To assess functional impacts of the VF-DMPs, the association between VF and gene expression was determined at the genes annotated to the VF-DMPs and an association analysis was carried out to determine whether methylation at the VF-DMPs is associated with gene expression. Further epigenetic analyses were carried out to compare methylation levels at the VF-DMPs as the response variables and a range of different metabolic health phenotypes including android:gynoid fat ratio (AGR), lipids, blood metabolomic profiles, insulin resistance, T2D and dietary intake variables. The results from all analyses were integrated to identify signals that exhibit altered SAT function and have strong relevance to metabolic health. RESULTS: We identified 1181 CpG positions in 788 genes to be differentially methylated with VF (VF-DMPs) with significant enrichment in the insulin signalling pathway. Follow-up cross-omic analysis of VF-DMPs integrating genetics, gene expression, metabolomics, diet, and metabolic traits highlighted VF-DMPs located in 9 genes with strong relevance to metabolic disease mechanisms, with replication of signals in FASN, SREBF1, TAGLN2, PC and CFAP410. PC methylation showed evidence for mediating effects of diet on VF. FASN DNA methylation exhibited putative causal effects on VF that were also strongly associated with insulin resistance and methylation levels in FASN better classified insulin resistance (AUC=0.91) than BMI or VF alone. CONCLUSIONS: Our findings help characterise the adiposity-associated methylation signature of SAT, with insights for metabolic disease risk.

Molecular remodeling of adipose tissue is associated with metabolic recovery after weight loss surgery.

BACKGROUND: Bariatric surgery is an effective therapy for individuals with severe obesity to achieve sustainable weight loss and to reduce comorbidities. Examining the molecular signature of subcutaneous adipose tissue (SAT) following different types of bariatric surgery may help in gaining further insight into their distinct metabolic impact. RESULTS: Subjects undergoing biliopancreatic diversion with duodenal switch (BPD-DS) showed a significantly higher percentage of total weight loss than those undergoing gastric bypass or sleeve gastrectomy (RYGB + SG) (41.7 ± 4.6 vs 28.2 ± 6.8%; p = 0.00005). Individuals losing more weight were also significantly more prone to achieve both type 2 diabetes and dyslipidemia remission (OR = 0.75; 95%CI = 0.51-0.91; p = 0.03). Whole transcriptome and methylome profiling showed that bariatric surgery induced a profound molecular remodeling of SAT at 12 months postoperative, mainly through gene down-regulation and hypermethylation. The extent of changes observed was greater following BPD-DS, with 61.1% and 49.8% of up- and down-regulated genes, as well as 85.7% and 70.4% of hyper- and hypomethylated genes being exclusive to this procedure, and mostly associated with a marked decrease of immune and inflammatory responses. Weight loss was strongly associated with genes being simultaneously differentially expressed and methylated in BPD-DS, with the strongest association being observed for GPD1L (r2 = 0.83; p = 1.4 × 10-6). CONCLUSIONS: Present findings point to the greater SAT molecular remodeling following BPD-DS as potentially linked with higher metabolic remission rates. These results will contribute to a better understanding of the metabolic pathways involved in the response to bariatric surgery and will eventually lead to the development of gene targets for the treatment of obesity. Trial registration ClinicalTrials.gov NCT02390973.